1 -Substituted 1,2-dihydro-1,3,5-triazines

When a tautomeric equilibrium is possible, neutral dihydro-1,3,5-triazines exist predominantly or exclusively in their 1,2-dihydro forms. Thus, the formation of 1-substituted 1,2-dihydro-1,3,5-triazines 104 was reported on intramolecular cyclization of imidoylcarbodiimides (86CB3737). No corresponding 1,4-dihydro tautomers were observed by H, NMR, or IR spectroscopy in solution. 

When N -substituted dihydro-1,2,3-triazines are formed, the produets exist solely in 1,6-dihydro forms 91 as eonfirmed by H and C NMR studies [96H(43)1759]. 

These authors found that nucleophilic additions to the unsubstituted ring system 1 can be carried out to yield a number of 7-substituted dihydro products or, in some cases, where an oxidation can follow this addition, also 7-substituted heteroaromatic derivatives (Scheme 6). Thus, reaction of 1 with indole under acidic conditions (in trifluoroacetic acid) yields 7-(177-indol-3-yl)-7,8-dihydrotetrazolo[l,5- ][l,2,4]triazine 24 <1998ZOR450>. Reaction of 1 with 3,4-difluoroacetophenone in the presence of potassium /frt-butoxide in tetrahydrofuran followed by... 

N-l, N-2- and 7V-4-substituted amidrazones (358)-(360) can be used for the synthesis of 1-, 2-, or 4-substituted dihydro-1,2,4-triazines <82CB2807>. Reactions of 1,2-dicarbonyl compounds with hydrazidines (361) have been used for the synthesis of 4-amino-dihydro-1,2,4-triazines <85LA78>. The examples shown (Scheme 67), employing the cyclopentanedione (362), result in a variety of reduced cyclopenta[c]-l, 2,4-triazines. 

Phenanthro[l,2-d][l,2,3]selenadiazole, 10,11 dihydro- H NMR, 6, 348 synthesis, 6, 353 Phenanthro[b]thiophenes synthesis, 4, 914 Phenanthro[4,5-bcd]thiophenes synthesis, 4, 883, 907, 914 Phenanthro[9,10-ej[l, 2,4]triazines synthesis, 3, 434 Phenarsazin synthesis, 1, 561 Phenazine dyes, 3, 196-197 nitration, 3, 177 UV Spectra, 2, 127 Phenazine, 3-amino-2-hydroxy-in colour photography, 1, 374 Phenazine, 1-chloro-nucleophilic substitution, 3, 164-165 5-oxide... 

Hydrolytic cleavage of the methylmercapto group usually proceeds very readily and in practically quantitative yield even on short boiling in water acidified with a few drops of hydrochloric acid. The readiness of the hydrolysis can be affected very substantially by substitution as shown in the case of 4-methyl-3-methylmercapto-5-thioxo-4,5-dihydro-l,2,4-triazine which was hydrolyzed only with ZN hydrochloric acid. "... 

Base-catalyzed Dimroth rearrangements of l-aryl-4,6-diamino-1,3,5-triazines or triflic acid-induced decomposition of 6-anilino-1,3,5-triazines led to the formation of the corresponding substituted 1,2-dihydro-l,3,5-triazines, whose structure was established on the basis of H NMR spectra (93JHC849). 

Alternatively, cyclocondensation of 1,5-diaminotetrazole 1024 with gly-oxal and substituted glyoxals produced tetrazolo[ 1,5-6][l, 2,4]triazine 1025 (88JOC5371), which can be reduced to 7,8-dihydro derivative 1026 using Pd/C as a hydrogenating catalyst, but NaBH4 gave 5,6,7,8-tetrahydro derivative 1027. 

The one-pot, three-component synthesis of a 20-membered dihydrotri-azine hbrary was also dramatically accelerated through the use of microwave irradiation [79]. Heating a subset of substituted anilines, cyanoguanidine and acetone in the presence of concentrated hydrochloric acid for 35 min at 90 °C in a single-mode microwave reactor gave the corresponding 2,2-dimethyl-1,2-dihydro-s-triazine hydrochloride 51 in comparable yield to conventional conductive heating methods but in a much shorter reaction time and increased purity (Scheme 21). 

For the synthetic studies on the bicyclic 6-6 systems 1-3, with one ring junction nitrogen and five extra heteroatoms, refer to CHEC-II(1996) <1996CHEC-II(8)743>. In the studies of the newly available compounds, a one-pot procedure for the synthesis of [l,2,4]triazino-[4,3- ][l,2,4,5]tetrazine 4 derivatives is discussed below. Refluxing of hydrazonoyl halides 10 in chloroform (or ethanol) in the presence of triethylamine for 6h with either 4-amino-2,3-dihydro-6-substituted-3-thioxo-[l,2,4]triazin-5(4//)-ones 8 or 4-amino-3-methylthio-6-substituted-[l,2,4]-triazin-5(4//)-ones 9 yielded compounds 4 (Equation 1) <2000JPR342>. 

Studies have recently become available concerning the kinetics and mechanism of the isomerisation, in dilute aqueous solution, of dihydrotriazines of this type (e.g. 4,6-diamino-l-(3,5-dichlorophenyl)-l,2-dihydro-2,2-dimethyl-l,3,5-triazine), and of their degradation to substituted biguanides 683). 

Hydrolytic cleavage of condensed 1,2,3-triazine derivatives is normally a straightforward, high-jneld process which results in production of one or other of several distinct types of product. 3-Alkyl- and 3-aryl-3,4-dihydro-l,2,3-benzotriazines, for example, undergo facile hydrolysis in concentrated hydrochloric acid to give, via the diazonium compound, A(-alkyl- and W-aryl-substituted o-chlorobenzylamines (100, R = Cl). If the reaction is carried out in water or in dilute mineral acid, the corresponding -alkyl and iV-aryl-substituted o-hydroxybenzylamines (100, R = OH) are obtained. 

The 1,2,4-triazine ring of 3,4-dihydro-2-methyl-1,2,4-triazino[3,2-6]-quinazoline-3,10-dione (622) was formed when 3-amino-2-(substituted amino)quinazolin-4-one (621) was cyclized with ethyl pyruvate in acetic acid (86JHC833). 

Grignard reagents add to 1,2,4-triazines. Initial attack at the 5-position is favored (277 — 278 — 279) if this position is substituted the nucleophile adds to the 6-position, and finally to the 3-position. Starting from the parent 1,2,4-triazine, 3,5,6-triaryl-l,2,4-triazines (280) have been prepared by successive addition of Grignard reagents to the ring and oxidation of the dihydro-1,2,4-triazine so formed. 

Biguanides [H2NC( = NH)NHC( = NH)NH2] react with lactones, amides, ortho esters, esters, acid anhydrides and acid chlorides to produce a wide range of 6-substituted 2,4-diamino-1,3,5-triazines (515) (59HC(l3)i). Biguanides with carbodiimides, isothiocyanates and ketones give corresponding melamines, thiones and dihydro derivatives, respectively. 

Substituted 3-thioxo-l,2,4-triazin-5-ones (76 R4 = H) are stable toward sodium amalgam, but the 4-substituted derivatives (76 R2 = H) are reduced to the 1,6-dihydro compounds (282). Hydrogenation of (76 R2 = H) affords ring-opened products. 3-Methyl-thio-l,2,4-triazin-5-ones (78) are reduced by sodium amalgam to 3-methylthio-3,4-dihydro-... 

Many 1,2,4-triazines form complexes with metal ions and can be used for their determination. Thus, 3- and/or 5-(2-pyridyl)-substituted 1,2,4-triazines (e.g. 820) can be used for the determination of iron (II), cobalt(II), nickel(II), zinc(II) and copper(I) ions, thallium and palladium ions can be analyzed by 6-phenyl- (821a) and 5,6-diphenyl-l,2,4-triazine-3-thione (821b), while osmium can be determined by 3-thioxo-l,2,4-triazin-5-one (822), 3-thioxo-dihydro-l,2,4-triazin-5-one (823), 6-mercapto-l,2,4-triazine-3,5-dione (824a), 6-mercapto-5-thioxo-l,2,4-triazin-3-one (824b) and 3,5-dithioxo-l,2,4-triazine-6-carboxyl-ates (825) <78HC(33)189, p. 1004). 

The role of drug-membrane interactions in overcoming, or at least in reducing, resistance will be discussed using two examples of antibacterials. A series of 5-(substituted) benzyl-2,4-diaminopyrimidines and 4,6-diamino-l,2-dihydro-2,2-dimethyl-l-(3-substituted)phenyl-s-triazines, inhibitors of dihydrofolate reductase (DHFR), were tested against sensitive and resistant E. coli cell cultures as well as against E. coli-derived DHFR [55] and compared with the effect on sensitive and resistant murine tu-... 

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